Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2001-01-04
2003-07-01
Peselev, Elli (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S018500, C536S127000
Reexamination Certificate
active
06586576
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to methods of preparing antibiotics, and more particularly to a new method for the crystallization of azithromycin dihydrate.
BACKGROUND OF THE INVENTION
Azithromycin, 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A, has the structural formula
and is a semi-synthetic macrolide antibiotic related to erythromycin A. Azithromycin possesses broad-antibacterial activity, and is useful for treating infections caused by susceptible microorganisms.
U.S. Pat. Nos. 4,517,359 and 4,474,768 describe methods for the preparation of azithromycin. According to European Patent Application EP 298 650 (“the EP '650 application”), the azithromycin obtained by the methods of U.S. Pat. Nos. 4,517,359 and 4,474,768 is a hygroscopic monohydrate. Because of its hygroscopic nature, the azithromyycin monohydrate is difficult to prepare and maintain in a form having a constant, reproducible water-content, and is particularly difficult to handle during formulation. The EP '650 application describes a dihydrate form of azithromycin that is less hygroscopic than the previously known azithromycin monohydrate. The method described in the EP '650 application for making the dihydrate form from the monohydrate is by crystallization from tetrahydrofuran, hexane and water. It would be advantageous to be able to manyfacture azithromycin dihydrate by a process which uses less potentially toxic solvents.
Chinese Patent Application CN 1,093,370 (“the Chinese '370 application”) describes an azithromycin crystal having water content of 4-6% and is characterized therein as being less hygroscopic than the dihydrate described in the EP '650 application. The method disclosed in the Chinese '370 application for making the described form of azithromycin is by crystallization from acetone and water.
A solvent system of acetone and water is also described in the European Patent application 941,999 wherein azithromycin dihydrate is precipitated from the acid salt by the addition of base. It is known from the relevant literature that azithromycin is not stable under acidic conditions and therefore potential undesirable impurities may be obtained by the precipitation method described by the EP '999 application.
Thus, there remains a need for a method of making azithromycin dihydrate in high yields directly from crude azithromycin (without the need to first isolate the monohydrate), under non-acidic conditions which does not necessitate the use of solvent which have potential toxicity problems in the production of pharmaceutical products.
By conventional methods of manufacture, azithromycin may contain isomers of azithromycin in about 0.5% to about 1%. It would be advantageous to have a method of removing possible isomers from azithromycin such that the purity of azithromycin dihydrate may be enhanced.
By conventional methods of manufacture, azithromycin may contain an impurity which is a derivative of azithromycin. It would be advantageous to have a method of making azithromycin which is substantially free of impurities that are derivatives of azithromycin.
SUMMARY OF THE INVENTION
The present invention relates to a process for making azithromycin dihydrate, comprising the steps of: (a) dissolving azithromycin in acetone; (b) maintaining the solution of azithromycin and acetone temperature of about 20° C. to about 25° C.; (c) adding water in two separate sequential additions, a first addition of water and a second addition of water; (d) adding water in the second addition step at a rate of up to 0.2 volumes of water per volume of acetone per hour; and (e) isolating the crystals of azithromycin dihydrate. Preferably, between about 0.4 to about 0.5 volumes of water per volume of water are added in the first addition of water. Preferably, the first addition of the water occurs over about 2 to about 3 hours. Preferably, the solution formed after the first addition of water is stirred for about 4 hours prior to the second addition of water. Preferably, the isolated azithromycin dihydrate contains less than 0.1% of isomers of azithromycin. More preferably, the isolated azithromycin dihydrate contains less than about 0.05 to about 0.02% of isomers of azithromycin. Most preferably, the isolated azithromycin dihydrate is substantially free of isomers of azithromycin.
The present invention relates to a method of making azithromycin from desmethyl-azithromycin comprising the steps of: (a) dissolving desmethyl-azithromycin in acetone; (b) refluxing the desmethyl-azithromycin acetone solution; (c) adding formaldehyde; (d) adding formic acid; (e) adding activated carbon; (f) adding sodium hydroxide to induce precipitation of azithromycin; and isolating azithromycin. Preferably, the isolated azithromycin is substantially free of derivatives of azithromycin.
The methods of the present invention are thus useful for the manufacture of azithromycin dihydrate in high yield and purity.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides new processes for the manufacture of azithromycin dihydrate wherein azithromycin dihydrate is made directly from crude azithromycin, under non-acidic conditions in unexpectedly high yields. Azithromycin for use as a starting material in the presently claimed method may be prepared according to the methods set forth in U.S. Pat. Nos. 4,517,359 and 4,474,768, the contents of which are incorporated herein by reference.
It has been discovered that in making azithromycin dihydrate by crystallization from acetone and water, that both (i) the temperature for the addition of water to a solution of acetone and azithromycin, and (ii) the addition profile for water during the precipitation process are essential. Further, it has been discovered that the present process for making azithromycin dihydrate, the purity of azithromycin is enhanced by the removal of isomers of azithromycin that may be present in the starting material.
Specifically, it has been discovered that for the precipitation of azithromycin dihydrate from acetone and water, the optimal temperature for addition of the water is from about 20° C. to about 25° C.; and that prior to precipitation of azithromycin dihydrate, about 0.4 to about 0.5 volumes of water to about 1 volume of acetone are added to the acetone solution over a time period of at least 2 hours. Additional water should be added only after definite crystals of azithromycin dihydrate are observed. The addition profile for water includes two separate sequential additions of water, a first addition of water, and a second addition of water. The final ratio of acetone:water should about 0.5 to about 1.5, preferably, not less than 1:1.
By the process of the present invention, azithromycin is dissolved in acetone. The temperature of the azithromycin solution is maintained at a range of about 20° C. to about 25° C. Preferably, the temperature is maintained at about 20° C. In the first addition of water to the acithromycin solution, water is added to the azithromycin solution with stirring such that crystallization of the azithromycin begins and a suspension is formed. The azithromycin solution formed following the first addition of water is stirred for at least two hours, preferably the reaction is stirred for about 2 to about 3 hours. Preferably, during the first addition of water, about 0.4 to about 0.5 volumes of water are added per volume of acetone to induce formation of a suspension. The resulting suspension is stirred until definite crystals of azithromycin dihydrate are observed and before any additional water is added. Preferably, the suspension which forms after the first addition of water is stirred for about 4 hours before additional water is added. After the suspension is formed, there is a second addition of water wherein water is added to complete the formation of azithromycin dihydrate crystals at a rate of up to 0.2 volumes of water per volume of acetone per hour after the suspension is formed. Azithromycin dihydrate is isolated by filtration followed by drying. The present method provides for hig
Aronhime Judith
Pesachovich Michael
Singer Claude
Kenyon & Kenyon
Peselev Elli
Teva Pharmaceutical Industries LTD
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